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Cureus Mar 2024The use of tyrosine kinase inhibitors (TKIs) has become the mainstay of treatment in patients suffering from chronic myeloid leukemia (CML), an adult leukemia caused by... (Review)
Review
The use of tyrosine kinase inhibitors (TKIs) has become the mainstay of treatment in patients suffering from chronic myeloid leukemia (CML), an adult leukemia caused by a reciprocal translocation between chromosomes 9 and 22, which creates an oncogene resulting in a myeloproliferative neoplasm. These drugs function by inhibiting the ATP-binding site on the fusion oncoprotein and subsequently halting proliferative activity. The goal of this work is to investigate the current state of research into genetic factors that influence the efficacy of four FDA-approved TKIs used to treat CML. This overview attempts to identify genetic criteria that could be considered when choosing one drug over the others and to identify where more research is needed. Our results suggest that the usual liver enzymes impacting patient response may not be a major factor affecting the efficacy of imatinib, nilotinib, and bosutinib, and yet, that is where most of the past research has focused. More research is warranted on the impact that human polymorphisms of the CYP enzymes have on dasatinib. The impact of polymorphisms in UGT1A1 should be investigated thoroughly in other TKIs, not only nilotinib. The role of influx and efflux transporters has been inconsistent thus far, possibly due to failures to account for the multiple proteins that can transport TKIs and the impact that tumors have on transporter expression. Because physicians cannot currently use a patient's genetic profile to better target their treatment with TKIs, it is critical that more research be conducted on auxiliary pathways or off-target binding effects to generate new leads for further study. Hopefully, new avenues of research will help explain treatment failures and improve patient outcomes.
PubMed: 38646295
DOI: 10.7759/cureus.56545 -
Cureus Mar 2024Patients with long-standing autoimmune diseases like systemic lupus erythematosus (SLE) are at a higher risk of developing hematological malignancies. However, chronic...
A Rare Case of Dual Metachronous Primary Malignancies, Chronic Myeloid Leukemia, and Tongue Carcinoma in a Patient With Long-Standing Systemic Lupus Erythematosus: A Case Report and Review of Literature.
Patients with long-standing autoimmune diseases like systemic lupus erythematosus (SLE) are at a higher risk of developing hematological malignancies. However, chronic myeloid leukemia (CML) has rarely been reported in patients with SLE. Advancements in medical diagnostics and treatment have led to the life expectancy of SLE and CML patients moving closer to that of the general population, and it is not uncommon to encounter more than one malignancy in a cancer survivor. Although squamous cell carcinoma (SCC) of the skin has been reported in CML patients, mucosal SCC of the head and neck has rarely only been reported in CML survivors. The objective of this case report is to share our experience in treating a patient with dual metachronous primary malignancies, CML, and tongue carcinoma, along with long-standing SLE, managed by a multidisciplinary team.
PubMed: 38646281
DOI: 10.7759/cureus.56648 -
Journal of Biomedical Science Apr 2024High levels of neutrophil extracellular trap (NET) formation or NETosis and autoantibodies are related to poor prognosis and disease severity of COVID-19 patients. Human...
BACKGROUND
High levels of neutrophil extracellular trap (NET) formation or NETosis and autoantibodies are related to poor prognosis and disease severity of COVID-19 patients. Human angiotensin-converting enzyme 2 (ACE2) cross-reactive anti-severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain (SARS-CoV-2 RBD) antibodies (CR Abs) have been reported as one of the sources of anti-ACE2 autoantibodies. However, the pathological implications of CR Abs in NET formation remain unknown.
METHODS
In this study, we first assessed the presence of CR Abs in the sera of COVID-19 patients with different severity by serological analysis. Sera and purified IgG from CR Abs positive COVID-19 patients as well as a mouse monoclonal Ab (mAb 127) that can recognize both ACE2 and the RBD were tested for their influence on NETosis and the possible mechanisms involved were studied.
RESULTS
An association between CR Abs levels and the severity of COVID-19 in 120 patients was found. The CR Abs-positive sera and IgG from severe COVID-19 patients and mAb 127 significantly activated human leukocytes and triggered NETosis, in the presence of RBD. This NETosis, triggered by the coexistence of CR Abs and RBD, activated thrombus-related cells but was abolished when the interaction between CR Abs and ACE2 or Fc receptors was disrupted. We also revealed that CR Abs-induced NETosis was suppressed in the presence of recombinant ACE2 or the Src family kinase inhibitor, dasatinib. Furthermore, we found that COVID-19 vaccination not only reduced COVID-19 severity but also prevented the production of CR Abs after SARS-CoV-2 infection.
CONCLUSIONS
Our findings provide possible pathogenic effects of CR Abs in exacerbating COVID-19 by enhancing NETosis, highlighting ACE2 and dasatinib as potential treatments, and supporting the benefit of vaccination in reducing disease severity and CR Abs production in COVID-19 patients.
Topics: Humans; Animals; Mice; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; COVID-19 Vaccines; Dasatinib; Immunoglobulin G; Autoantibodies; Spike Glycoprotein, Coronavirus; Protein Binding
PubMed: 38637878
DOI: 10.1186/s12929-024-01026-5 -
Annals of Hematology Jun 2024Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the...
Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.
Topics: Humans; Dasatinib; Male; Female; Middle Aged; Protein Kinase Inhibitors; Aged; Pleural Effusion; Adult; Incidence; Leukemia, Myeloid, Chronic-Phase; Aged, 80 and over; Quinolines; Nitriles; Drug Substitution; Aniline Compounds; Imatinib Mesylate; Young Adult; Retrospective Studies; Pyrimidines
PubMed: 38634915
DOI: 10.1007/s00277-024-05760-6 -
Toxicology May 2024Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury,...
Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21 hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available single-nuclei RNAseq data, we identified a subpopulation of p21 hepatocytes enriched in a unique secretome of factors, such as CXCL14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21 hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, CXCL14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or CXCL14 with a neutralizing antibody. We found that targeting CXCL14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting senescent hepatocytes had no effect. These data support the conclusion that the sustained induction of p21 in hepatocytes with persistent CXCL14 secretion are critical mechanistic events leading to ALF in mice and human patients.
Topics: Acetaminophen; Animals; Hepatocytes; Humans; Male; Chemical and Drug Induced Liver Injury; Cyclin-Dependent Kinase Inhibitor p21; Female; Mice; Chemokines, CXC; Mice, Inbred C57BL; Liver Regeneration; Drug Overdose; Analgesics, Non-Narcotic
PubMed: 38614205
DOI: 10.1016/j.tox.2024.153804 -
International Journal of Molecular... Apr 2024The tumor microenvironment (TME) plays an essential role in tumor progression and in modulating tumor response to anticancer therapy. Cellular senescence leads to a...
The tumor microenvironment (TME) plays an essential role in tumor progression and in modulating tumor response to anticancer therapy. Cellular senescence leads to a switch in the cell secretome, characterized by the senescence-associated secretory phenotype (SASP), which may regulate tumorigenesis. Senolytic therapy is considered a novel anticancer strategy that eliminates the deleterious effects of senescent cells in the TME. Here, we show that two different types of senolytic drugs, despite efficiently depleting senescent cells, have opposite effects on cancer-associated fibroblasts (CAFs) and their ability to regulate epithelial-mesenchymal transition (EMT). We found that senolytic drugs, navitoclax and the combination of dasatinib/quercetin, reduced the number of spontaneously senescent and TNF-induced senescent CAFs. Despite the depletion of senescent cells, the combination of dasatinib/quercetin versus navitoclax increased the secretion of the SASP pro-inflammatory cytokine IL-6. This differential effect correlated with the promotion of enhanced migration and EMT in MC38 colorectal cancer cells. Our results demonstrate that some senolytics may have side effects unrelated to their senolytic activity and may promote tumorigenesis. We argue for more careful and extensive studies of the effects of senolytics on various aspects of tumor progression and tumor resistance to therapy before the senolytic strategy is implemented in the clinic.
Topics: Humans; Senotherapeutics; Cancer-Associated Fibroblasts; Dasatinib; Quercetin; Carcinogenesis; Cell Transformation, Neoplastic; Epithelial-Mesenchymal Transition; Cytokines; Tumor Microenvironment; Aniline Compounds; Sulfonamides
PubMed: 38612842
DOI: 10.3390/ijms25074031 -
Cancers Mar 2024B cell acute lymphoblastic leukemia (B-ALL) is characterized by an accumulation of malignant precursor cells. Treatment consists of multiagent chemotherapy followed by...
B cell acute lymphoblastic leukemia (B-ALL) is characterized by an accumulation of malignant precursor cells. Treatment consists of multiagent chemotherapy followed by allogeneic stem cell transplantation in high-risk patients. In addition, patients bearing the BCR-ABL1 fusion gene receive concomitant tyrosine kinase inhibitor (TKI) therapy. On the other hand, monoclonal antibody therapy is increasingly used in both clinical trials and real-world settings. The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839). The efficacy of monoclonal antibodies is based, at least in part, on their ability to induce antibody-dependent cellular cytotoxicity (ADCC). Combination treatments, e.g., chemotherapy and TKI, should therefore be screened for potential interference with ADCC. Here, we report on in vitro data using BCR-ABL1 positive and negative B-ALL cell lines treated with rituximab and TKI. NK cell activation, proliferation, degranulation, cytokine release and tumor cell lysis were analyzed. In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.
PubMed: 38610966
DOI: 10.3390/cancers16071288 -
Molecular Human Reproduction Apr 2024Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the...
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated β-galactosidase and the SASP-related factor interleukin-6 was significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS, and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.
Topics: Polycystic Ovary Syndrome; Female; Cellular Senescence; Humans; Animals; Granulosa Cells; Quercetin; Mice; Senescence-Associated Secretory Phenotype; Adult; Dasatinib; Disease Models, Animal; Senotherapeutics; Hyperandrogenism; Interleukin-6; Dehydroepiandrosterone
PubMed: 38603629
DOI: 10.1093/molehr/gaae015 -
Blood Advances Jun 2024The t(1;19) translocation, encoding the oncogenic fusion protein E2A (TCF3)-PBX1, is involved in acute lymphoblastic leukemia (ALL) and associated with a pre-B-cell...
The t(1;19) translocation, encoding the oncogenic fusion protein E2A (TCF3)-PBX1, is involved in acute lymphoblastic leukemia (ALL) and associated with a pre-B-cell receptor (preBCR+) phenotype. Relapse in patients with E2A-PBX1+ ALL frequently occurs in the central nervous system (CNS). Therefore, there is a medical need for the identification of CNS active regimens for the treatment of E2A-PBX1+/preBCR+ ALL. Using unbiased short hairpin RNA (shRNA) library screening approaches, we identified Bruton tyrosine kinase (BTK) as a key gene involved in both proliferation and dasatinib sensitivity of E2A-PBX1+/preBCR+ ALL. Depletion of BTK by shRNAs resulted in decreased proliferation of dasatinib-treated E2A-PBX1+/preBCR+ cells compared with control-transduced cells. Moreover, the combination of dasatinib with BTK inhibitors (BTKi; ibrutinib, acalabrutinib, or zanubrutinib) significantly decreased E2A-PBX1+/preBCR+ human and murine cell proliferation, reduced phospholipase C gamma 2 (PLCG2) and BTK phosphorylation and total protein levels and increased disease-free survival of mice in secondary transplantation assays, particularly reducing CNS-leukemic infiltration. Hence, dasatinib with ibrutinib reduced pPLCG2 and pBTK in primary ALL patient samples, including E2A-PBX1+ ALLs. In summary, genetic depletion and pharmacological inhibition of BTK increase dasatinib effects in human and mouse with E2A-PBX1+/preBCR+ ALL across most of performed assays, with the combination of dasatinib and BTKi proving effective in reducing CNS infiltration of E2A-PBX1+/preBCR+ ALL cells in vivo.
Topics: Dasatinib; Agammaglobulinaemia Tyrosine Kinase; Humans; Animals; Mice; Protein Kinase Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Central Nervous System Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Oncogene Proteins, Fusion; Cell Line, Tumor; Cell Proliferation
PubMed: 38598725
DOI: 10.1182/bloodadvances.2023011582 -
Archives of Toxicology Jul 2024Oxaliplatin (OHP) is effective in colorectal cancer treatment but induces peripheral neurotoxicity (OHP-induced peripheral neurotoxicity, OIPN), diminishing survivor...
Oxaliplatin (OHP) is effective in colorectal cancer treatment but induces peripheral neurotoxicity (OHP-induced peripheral neurotoxicity, OIPN), diminishing survivor quality of life. Organic cation transporter 2 (OCT2) is a key OHP uptake pathway in dorsal root ganglia. Competing for OCT2-mediated OHP uptake, such as with the tyrosine kinase inhibitor dasatinib, may mitigate OHP side effects. We investigated OHP and dasatinib interaction with OCT2 in human embryonic kidney 293 (HEK293) cells expressing OCT2 within a 10 to 10 M concentration range. Uptake competition experiments using fluorescent organic cation 4-(4-dimethylaminostyryl)-N-methylpyridinium (ASP, 1 µM) and mass spectrometry (MS) to determine cellular platinum content indicated that OHP (100 µM) is an OCT2 substrate, mediating OHP cellular toxicity. ASP and MS analysis revealed dasatinib as a non-transported inhibitor of hOCT2 (IC = 5.9 µM) and as a regulator of OCT2 activity. Dasatinib reduced transporter V, potentially via Y544 phosphorylation suppression. MS analysis showed cellular dasatinib accumulation independent of hOCT2. Although 3 µM dasatinib reduced 100 µM OHP accumulation in hOCT2-HEK293 cells, co-incubation with dasatinib and OHP did not prevent OHP toxicity, possibly due to dasatinib-induced cell viability reduction. In summary, this study demonstrates OHP as an OCT2 substrate and dasatinib as a non-transported inhibitor and regulator of OCT2, offering potential for OIPN mitigation.
Topics: Humans; Dasatinib; HEK293 Cells; Oxaliplatin; Organic Cation Transporter 2; Antineoplastic Agents; Protein Kinase Inhibitors; Drug Interactions; Pyridinium Compounds; Tyrosine Kinase Inhibitors
PubMed: 38589558
DOI: 10.1007/s00204-024-03742-1